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Fcg Receptor IIa and IIIa Polymorphisms Are Associated with the Risk of HIV Infection
Donald Forthal*1, G Landucci1, T Phan1, R Higa-Tanner1, and P Gilbert2
1Univ of California Sch of Med, Irvine, US and 2Statistical Ctr for HIV/AIDS Res and Prevention, Fred Hutchinson Cancer Res Ctr, Seattle, WA, US
Background: The biological activity of antibody is often
mediated by interactions between antibody Fc and Fc receptors for
immunoglobulin-G (IgG) (FcγR). Genetic polymorphisms in FcγR affect
IgG binding and are associated with clinical outcomes in infectious and
autoimmune diseases and in monoclonal antibody immunotherapy. We determined if
polymorphisms in FcγRIIa (histidine [H] or arginine [R] at amino acid 131)
or in FcγRIIIa (valine [V] or phenylalanine [F] at amino acid 158)
influenced risk of infection among rgp120 vaccine or placebo recipients in the
VAX004 trial.
Methods: Allele-specific primers were used to genotype
223 infected and 289 randomly sampled uninfected vaccinees and 108 infected and
152 randomly sampled uninfected placebo recipients.
Results: Among placebo recipients, there were no
associations between infection risk and the IIa or IIIa genotype when each gene
was analyzed separately. However, the combined IIa/IIIa HHVV genotype (5% of
the population studied) was associated with a 6-fold decrease in risk of
infection compared with other genotypes (p
= 0.03). Among vaccinees, the HHVV genotype was associated with a 2.4-fold
increase in infection risk (p =
0.04). Possessors of HHVV had a 12.8 times greater risk of infection if they
were vaccinated than if they received placebo (p = 0.01). Among infected vaccinees, last pre-infection HIVMN-neutralizing
titers in HHVV were not different than titers in other genotypes (p = 0.5). However, titers of
vaccine-induced antibodies were higher in infected HHVV vaccinees than in
uninfected HHVV vaccinees (comparing last pre-infection HIVMN-neutralizing
titers in infected subjects with titers of uninfected subjects obtained after
either the third [p = 0.02], fourth [p = 0.04], or fifth [p = 0.1] immunization).
Conclusions: The
HHVV genotype may confer protection against sexually transmitted HIV infection
in the absence of vaccine-induced antibody. However, after vaccination,
individuals with the HHVV genotype are more likely to become infected than those
with other genotypes. Thus, rgp120 vaccine appears to enhance the likelihood of
infection among HHVV. It is known that HH and VV FcγR bind immune
complexes with higher avidity than other genotypes. We found that
vaccine-induced antibody titers are higher in infected HHVV vaccinees than in
uninfected HHVV vaccinees. These facts support an in vivo role for vaccine-induced antibody-dependent enhancement of
HIV infection involving FcγRIIa and IIIa.
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